1. Field of the Invention
The present invention relates to lower urinary tract dysfunctions in mammals, and particularly, to compositions and methods of treating urinary tract disorders using delta opioid receptor agonists to modulate contraction and relaxation of muscles controlling micturition.
2. Description of the Related Art
The National Kidney and Urologic Diseases Advisory Board estimates that urinary incontinence (UI) affects approximately 17 million people in the United States. Incontinence is a word that many people associate with the aging process. However, incontinence is not a natural part of the aging process. It can happen at any age and may be due to a number of causes, including, infection, effects of medication, muscle weakness, hormone imbalance, neurological disorders and immobility. Incontinence remains largely a neglected problem because affected people may feel embarrassed, isolated, stigmatized and unwilling to discuss the problem.
Continence requires input from the central nervous system (CNS) and integrity of lower urinary tract function. The role of the CNS is complex and not fully understood, however, it is believed that the parasympathetic, sympathetic and somatic nerves innervate the main structures involved in the maintenance of continence. The physiology of micturition (urination) is complex; however a basic understanding is necessary to appreciate the etiology and treatment of incontinence. As urine fills the bladder via the ureter, the detrusor muscle stretches allowing the bladder to expand. As the bladder fills, stretch receptors within the bladder wall are stimulated, giving the brain information regarding the amount of urine within the bladder. With low bladder volumes, the sympathetic nervous system is stimulated and parasympathetic system is inhibited resulting in internal sphincter contraction and detrusor relaxation. When the bladder is full and micturition is desired, the inhibitory signals from the brain are replaced by impulses that stimulate the parasympathetic system resulting in detrusor contraction, and inhibit the sympathetic system resulting in internal sphincter relaxation. The intravesicle pressure then rises to a point at which it exceeds the resistance within the urethra, and urine flows out of the bladder. Once the bladder is emptied, the brain again sends impulses resulting in parasympathetic inhibition and sympathetic stimulation resulting in detrusor relaxation and internal sphincter contraction. The urinary bladder is again ready to be filled with urine. Thus, because the lower urinary tract function involves so many CNS systems, the impact of medication and diseases is often difficult to predict.
Different types of urinary tract dysfunctions exhibit different symptoms. For example, dysuria includes urinary frequency, nocturia and urgency, and may be caused by cystitis, prostatitis, benign prostatic hypertrophy (BPH) or neurological disorders. Enuresis refers to the involuntary passage of urine at night or during sleep.
After the type and cause of the urinary tract dysfunction has been determined, treatment can follow, which may variously include behavioral, surgical and/or pharmacological therapeutic approaches. Behavioral therapy may include muscle exercise, adjustment of the timing or amount of fluid ingested, and/or prompted voiding. However, such methods are dependent on motivation and in some settings, such as institutions, the dedication of the nursing staff in charge of the management of incontinent patients.
Surgery may be required to correct certain disorders, such as blockage, enlarged prostate, and weak pelvic muscles but surgery is considered a last resort because of the inherent complications that may occur concurrently with surgery.
Drug therapy is more widely used as a urinary tract dysfunction-combating approach in place of behavioral therapy and surgery. A variety of therapeutic drugs have been used, including: alpha-adrenergic agonists, such as phenylpropanolamine and pseudoephedrin; anticholinergics, such as oxybutynin, propantheline, dicyclomine and tolterodine; alpha-adrenergic antagonists, such as prazosin, terazosin and doxazosin; and tricyclic antidepressants. However, these drugs may not be effective for all patients. More importantly, negative side effects of these drugs, such as dry mouth, nausea, insomnia, weakness and/or fatigue, can halt treatment or impair patient compliance. Moreover, disease states or adverse interactions with other drugs may contraindicate the use of these compounds or require lower dosages that may not be effective to combat the urinary tract dysfunction.
Thus, present day drug therapy does not successfully solve the problems associated with urinary tract dysfunction. Accordingly, the art continues to search for improved pharmaceutical agents for treatment of urinary tract dysfunctions that can be used conveniently and without embarrassment, and that do not involve the problems associated with prior therapeutic methods.